The number of people who are at risk of acquiring malaria is not precisely known, however some estimates run as high as 3.2 billion people with up to 500 million clinical cases per year (Breman, J. G.; Egan, A.; Keusch, G. T. Am J Trop Med Hyg 2001, 64(1-2 Suppl), iv). Further, malaria contributes to the deaths of 1-3 million people per year (Wkly Epidemiol Rec 1997, 72(37), 277), most of them young children. The continued spread of resistance to antimalarials such as chloroquine (White, N. J.; Nosten, F.; Looareesuwan, S.; Watkins, W. M.; Marsh, K.; Snow, R. W.; Kokwaro, G.; Ouma, J.; Hien, T. T.; Molyneux, M. E.; Taylor, T. E.; Newbold, C. I.; Ruebush, T. K., 2nd; Danis, M.; Greenwood, B. M.; Anderson, R. M.; Olliaro, P. Lancet 1999, 353(9168), 1965) has produced a desperate need for safe and inexpensive anti-malarial agents with novel mechanisms of action. Previous work demonstrated that small sulfonated compounds inhibited the entry of merozoites of P. falciparum into human erythrocytes, and were also able to suppress the replication of P. berghei in mice (Kisilevsky, R.; Crandall, I.; Szarek, W. A.; Bhat, S.; Tan, C.; Boudreau, L.; Kain, K. C. Antimicrob Agents Chemother 2002, 46(8), 2619). The interactions between a merozoite and an erythrocyte that are responsible for the invasion process are complex (Pasvol, G. Trends Parasitol 2003, 19(10), 430); however individual Plasmodium species are frequently limited to a particular host, or even a particular stage of development of an erythrocyte, by the specificity of the ligand/receptor interactions involved in erythrocyte invasion (Pasvol, G.; Wainscoat, J. S.; Weatherall, D. J. Nature 1982, 297(5861), 64). The invasion process is rapid—typically 15-30 seconds (Barnwell, J. W.; Galinski, M. R. Invasion of Vertebrate Cells: Erythrocytes. In: Sherman I W, ed. Malaria: Parasite Biology, Pathogenesis, and Protection. Washington, D.C.: ASM Press, 1998: 93-123), and is divided frequently into three stages: 1) the initial attachment of the merozoite to the erythrocyte followed by reorientation of the merozoite such that its apical end is proximal to the erythrocyte; 2) the secretion and anchoring of proteins required to form a “tight junction” with the erythrocyte membrane; and 3) physical insertion (Oh, S. S.; Chishti, A. H. Curr Top Microbiol Immunol 2005, 295, 203). While the receptors required for tight junction formation are reasonably well characterized (Lobo, C. A.; de Frazao, K.; Rodriguez, M.; Reid, M.; Zalis, M.; Lustigman, S. Infect Immun 2004, 72(10), 5886) the identities of the molecules responsible for the initial contact events are less clear.
Babesia, which belong to the hematozoan class is similar to Plasmodium and are a particularly important class of animal and human parasites. Babesia usually cause animal disease, mainly infecting cattle and dogs. Babesia parasites are also known to infect humans (Hunfeld, K-P; et al. J. Clin. Microbiol. 2002, 40(7), 2431). The invasion of an erythrocyte by Babesia parasites is similar to that by Plasmodium species (Yokoyama, N.; Okamura, M. Igarashi, I., Veterinary Parasitology, 2006, 138, 22). Accordingly, agents that block the invasion of Plasmodium parasites are expected to also block the invasion of Babesia parasites.
A series of tetrazolium salts have been shown to have antimalarial activity (Cui, X., J. Z. Vlahakis, I. E. Crandall, and W. A. Szarek. 2008. Anti-Plasmodium activity of tetrazolium salts. Bioorg Med Chem 16:1927-1947).
A series of thiazolium salts have been shown to have antimalarial activity (Hamzé, A. et al. J. Med. Chem. 2005, 48, 3643).